Despite advances in prostate cancer detection and treatment of primary disease, metastatic prostate cancer continues to be a leading cause of cancer deaths in men. Although metastatic disease typically responds to androgen deprivation, most men acquire androgen-independent (AI) disease within 2 years. Recent observations have suggested that sometimes AI disease remains responsive to further hormonal therapies. This may be because the androgen receptor (AR) is consistently expressed in AI cancers, implying that prostate cancer cells could conceivably remain sensitive to stimulation via this pathway. Work performed in this laboratory suggested that AI disease can sometimes be associated with AR mutations. Investigation of the in vitro phenotype of these mutants revealed that the antiandrogen bicalutamide was an effective antagonist. Based on these data, a clinical trial begun in June of 1995 using high-dose bicalutamide resulted in a 20% response rate without appreciable toxicity. The current proposal seeks to build on this finding by initiating adrenocortical suppression using aminoglutethimide and hydrocortisone at the time progression on bicalutamide. With further progression, bicalutamide will be discontinued to determine if patients demonstrate a bicalutamide- withdrawal response. As in our previous study, this trial is part of a larger undertaking that includes assessment of translational endpoints focusing on the expression and phenotype of the AR, and the hormonal environment following sequential hormonal maneuvers. The overall goals of this trial are to prolong and extend the period of prostate cancer's hormonal sensitivity and to enhance our understanding of the mechanisms mediating androgen-independence.